Amplification of Cardiac Motor Functions by Prestin (Slc26a5)

Abstract

The human heart is a durable biological motor, beating approximately 3.4 billion times in an 80-year lifespan. Actual cardiac performance originates in the function of cardiac myocytes, which are electromotile, changing in length in response to a change in membrane potentials. Groundbreaking work by Hugh Huxley and Jean Hanson et al. in the 1950s introduced the “sliding filament theory” that during muscle contraction, myosin and the filamentous actin protein form cross-bridges, allowing myosin to slide along actin, leading to length changes and force generation. Some muscle contraction mechanisms remain unexplained, such as how the sarcolemma accommodates ∼0.2-μm-displacement length changes per sarcomere per cardiac cycle without experiencing significant distortion. Here we invoke and test for the presence and function of a canonical non-conventional motor protein, prestin (Slc26a5), in cardiomyocytes as an amplifier of actin-myosin force generation. Prestin has been thought to be expressed exclusively in outer hair cells (OHCs) of the inner ear. It is a direct voltage-to-force convertor and mediates electromotility of OHCs as part of the molecular element of cochlear sound amplification. We hypothesize that prestin is expressed in mouse and human heart tissue and serves as the cardiac mechanical amplifier. We investigated whether the genetic deletion of Slc26a5 (Slc26a5-/-) produces in vivo and in vitro cardiac contractility changes. Multimodal Second Harmonic Generation (SHG) two-photon fluorescence microscopy and Stimulated Emission Depletion (STED) microscopy analyses were used to substantiate findings of the expression and functional roles of prestin in ventricular myocytes. We conclude that prestin serves to amplify actin-myosin force generation in cardiomyocytes, accounting for the non-linear properties of muscle contraction. The functional significance of prestin is underpinned by alterations of cardiac contractility in Slc26a5-/-mice. Our results suggest that prestin may serve as a broader cellular motor amplifier.